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Clinical Trial
. 2012 Aug;71(8):1289-96.
doi: 10.1136/annrheumdis-2011-200706. Epub 2012 Feb 2.

Safety and efficacy of ocrelizumab in combination with methotrexate in MTX-naive subjects with rheumatoid arthritis: the phase III FILM trial

William Stohl  1 , Juan Gomez-Reino, Ewa Olech, Jean Dudler, Roy M Fleischmann, Cristiano A F Zerbini, Ali Ashrafzadeh, Susanna Grzeschik, Rebecca Bieraugel, Jennifer Green, Steven Francom, Wolfgang Dummer
Affiliations
Free PMC article
Clinical Trial

Safety and efficacy of ocrelizumab in combination with methotrexate in MTX-naive subjects with rheumatoid arthritis: the phase III FILM trial

William Stohl et al. Ann Rheum Dis. 2012 Aug.
Free PMC article

Abstract

Objective: To determine the efficacy and safety of ocrelizumab (OCR) with methotrexate (MTX) in MTX-naive rheumatoid arthritis (RA) patients.

Methods: In a randomised, double-blind, controlled trial, patients received placebo+MTX (MTX; n=210), OCR 200 mg×2+MTX (OCR 200; n=200) or OCR 500 mg×2+MTX (OCR 500; n=203). OCR/placebo (two intravenous infusions) was given on days 1 and 15, with fixed re-treatment scheduled at weeks 24/26, 52/54 and 76/78. Due to early termination of OCR dosing, there was no formal primary end point analysis (change from baseline in modified total Sharp score (ΔmTSS) at week 104). Analyses are reported for week 52 outcomes.

Results: At week 52, treatment with OCR+MTX compared with MTX alone reduced progression of joint damage (mean (SD) change in ΔmTSS: OCR 200, 0.66 (4.51); OCR 500, 0.27 (2.91); MTX alone, 1.59 (4.82); p=0.001 and p=0.003, respectively vs MTX alone) and improved clinical signs and symptoms (American College of Rheumatology 20 response: OCR 200, 73.0%; OCR 500, 71.0%; MTX alone, 57.5%; p<0.005 for each OCR vs MTX alone). Serious infection rates per 100 patient-years were similar with OCR 200 and MTX alone (2.6 (95% CI 0.9 to 6.1) and 3.0 (1.1 to 6.5), respectively), but higher with OCR 500 (7.1 (3.9 to 11.9)).

Conclusions: OCR 200 mg and 500 mg with MTX in MTX-naive patients with RA were effective in inhibiting joint damage progression and improving RA signs and symptoms. OCR 500 mg with MTX was associated with an increased rate of serious infections.

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Conflict of interest statement

Competing interests: WS has received research grants from Xencor and is a site investigator for clinical trials in RA and systemic lupus erythematosus sponsored by Genentech/Roche, Pfizer and Human Genome Sciences. JG-R has served on advisory boards for Roche, and has received consultancy fees, grants and payment for lectures from Roche. EO has received grants, consultancy fees and payments for lectures from Genentech, and consultancy fees and grants from Roche. JD has served on advisory boards for Roche Switzerland, Merck Sharp Dohme Switzerland, Pfizer Switzerland, Amgen Switzerland, UCB Switzerland, Abbott Switzerland and Novartis Switzerland, has received consultancy fees from Roche Switzerland, Merck Sharp Dohme Switzerland and UCB Switzerland, has received payment for lectures from Roche, Pfizer, Merck Sharp Dohme, Abbott and UCB, has received payment for manuscript preparation from Roche Switzerland and Merck Sharp Dohme Switzerland, and has received travel/accommodation/meeting expenses from Roche Switzerland, Merck Sharp Dohme Switzerland, Bristol Myers Squibb Switzerland and Pfizer Switzerland. RMF has received research grants from Genentech and Roche. CZ has received consultancy fees and grants from Sanofi, Servier and Pfizer, and research grants from Lilly, Amgen, Roche and Merck. AA was an employee of Genentech and held Genentech stock options during the conduct of the study and manuscript preparation. SG is an employee of Genentech, owns Roche stock and holds Roche stock options. RB and JG are employees of Roche. SF is an employee of Genentech. WD is an employee of Genentech, owns Roche stock and holds Roche stock options.

Figures

Figure 1
Figure 1
(A) Study design. (B) Disposition of patients. *One patient withdrew from the study due to an AE. The patient died; the cause of death was ischaemic cerebral infarction. †Outcomes reported at week 52. AE, adverse event; ITT, intent-to-treat; mITT, modified ITT; MTX, methotrexate; OCR, ocrelizumab.
Figure 2
Figure 2
Radiographic outcomes at 52 weeks. (A) Changes in mTSS. All comparisons are to placebo using Van Elteren's test stratified by region and screening CRP status. Missing data were imputed using linear extrapolation. *p<0.05; **p≤0.001. (B) Proportion of patients with no radiological progression. Cochran–Mantel–Haenszel analysis was used to calculate p values. Analysis was stratified by region and screening CRP status. *p<0.05; **p≤0.001. (C) Cumulative distribution plot of change from baseline in mean change in mTSS. Missing data were imputed using linear extrapolation. CRP, C reactive protein; mTSS, van der Heijde-modified total Sharp score; MTX, methotrexate; OCR, ocrelizumab.
Figure 3
Figure 3
Clinical efficacy at 52 weeks. 95% CIs indicated. Cochran–Mantel–Haenszel analysis was used to calculate p values. Analysis was stratified by region and screening CRP status. Last observation carried forward to withdrawal or rescue for joint counts. *p<0.05; **p≤0.001; ***p≤0.0001. (A) ACR20/50/70 response rates. Missing change from baseline in CRP substituted with change from baseline in ESR. Observed data for other ACR components until withdrawal/rescue. (B) DAS28-ESR remission. (C) Proportion of patients with low Disease Activity Score (DAS28-ESR). Observed data for visual analogue scale and ESR until withdrawal/rescue. ACR, American College of Rheumatology; CRP, C reactive protein; DAS28-ESR, Disease Activity Score in 28 joints erythrocyte sedimentation rate; MTX, methotrexate; OCR, ocrelizumab.
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